Fragment-Sized Thiazoles in Fragment-Based Drug Discovery Campaigns: Friend or Foe?

Autor: Proj M; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia., Hrast M; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia., Knez D; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia., Bozovičar K; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia., Grabrijan K; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia., Meden A; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia., Gobec S; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia., Frlan R; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Nov 03; Vol. 13 (12), pp. 1905-1910. Date of Electronic Publication: 2022 Nov 03 (Print Publication: 2022).
DOI: 10.1021/acsmedchemlett.2c00429
Abstrakt: Thiazoles exhibit a wide range of biological activities and therefore represent useful and attractive building blocks. To evaluate their usefulness and pinpoint their liabilities in fragment screening campaigns, we assembled a focused library of 49 fragment-sized thiazoles and thiadiazoles with various substituents, namely amines, bromides, carboxylic acids, and nitriles. The library was profiled in a cascade of biochemical inhibition assays, redox activity, thiol reactivity, and stability assays. Our study indicates that when thiazole derivatives are identified as screening hits, their reactivity should be carefully addressed and correlated with specific on-target engagement. Importantly, nonspecific inhibition should be excluded using experimental approaches and in silico predictions. To help with validation of hits identified in fragment screening campaigns, we can apply our high-throughput profiling workflow to focus on the most tractable compounds with a clear mechanism of action.
Competing Interests: The authors declare no competing financial interest.
(© 2022 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE